Pulpitis constitutes a significant challenge in clinical management due to its impact on peripheral nerve tissue and the persistence of chronic pain. Despite its clinical importance, the correlation between neuronal activity and the expression of voltage-gated sodium channel 1.7 (Nav1.7) in the trigeminal ganglion (TG) during pulpitis is less investigated. The aim of this study was to examine the relationship between experimentally induced pulpitis and Nav1.7 expression in the TG and to investigate the potential of selective Nav1.7 modulation to attenuate TG abnormal activity associated with pulpitis. Acute pulpitis was induced at the maxillary molar (M1) using allyl isothiocyanate (AITC). The mice were divided into three groups: control, pulpitis model, and pulpitis model treated with ProTx-II, a selective Nav1.7 channel inhibitor. After three days following the surgery, we conducted a recording and comparative analysis of the neural activity of the TG utilizing in vivo optical imaging. Then immunohistochemistry and Western blot were performed to assess changes in the expression levels of extracellular signal-regulated kinase (ERK), c-Fos, collapsin response mediator protein-2 (CRMP2), and Nav1.7 channels. The optical imaging result showed significant neurological excitation in pulpitis TGs. Nav1.7 expressions exhibited upregulation, accompanied by signaling molecular changes suggestive of inflammation and neuroplasticity. In addition, inhibition of Nav1.7 led to reduced neural activity and subsequent decreases in ERK, c-Fos, and CRMP2 levels. These findings suggest the potential for targeting overexpressed Nav1.7 channels to alleviate pain associated with pulpitis, providing practical pain management strategies.

2023-08-01·European journal of pharmacology

An electrophysiological method for evaluation of topical antipruritic drugs on itch-related neuronal activities in the spinal cord in hairless mice

Article

作者: Ohtubo, Yoshitaka ; Ueda, Yuhki ; Uta, Daisuke ; Furue, Hidemasa

To evaluate the effects of antipruritic drugs, it is important to determine whether the neural responses induced by physiological itch stimuli are suppressed. Although there are several behavioral assessments for topical antipruritic drugs applied to the skin, there are few established methods at neuronal levels using in vivo electrophysiological recordings for predicting local efficacy of antipruritic drugs for cutaneous application. To establish an assessment of topical antipruritic drugs applied to skin using in vivo extracellular recording from neurons in the superficial dorsal horn, we examined the relationships between itch-related biting behavior and spinal neuronal responses elicited by intradermal injection of pruritogen serotonin (5-HT) in hairless mice. The efficacy of topical occlusive application of local anesthetics was also evaluated by an in vivo electrophysiological method. 5-HT significantly increased the firing frequency in spinal neurons. The spinal firing frequency time course was similar to that of the biting behavior after the 5-HT injections. The 5-HT-induced spinal responses were significantly decreased by topical occlusive application of lidocaine or a Nav 1.7 channel blocker to the calf. The intradermal 5-HT injection-induced spinal neuronal responses appeared to be suppressed by topical occlusive application of lidocaine or a Nav1.7 channel blocker. The electrophysiological method for evaluating topical antipruritic drugs may be beneficial in assessing local effects on the skin.

2023-01-01·Frontiers in molecular neuroscience

Ectopic expression of Nav1.7 in spinal dorsal horn neurons induced by NGF contributes to neuropathic pain in a mouse spinal cord injury model.

Article

作者: Zhu, Fengting ; Xia, Ruilong ; Xu, Dan ; Xia, Wei ; Fu, Yan ; Peng, Changgeng ; Sun, Liting ; Wen, Ting ; Yu, Xin

Neuropathic pain (NP) induced by spinal cord injury (SCI) often causes long-term disturbance for patients, but the mechanisms behind remains unclear. Here, our study showed SCI-induced ectopic expression of Nav1.7 in abundant neurons located in deep and superficial laminae layers of the spinal dorsal horn (SDH) and upregulation of Nav1.7 expression in dorsal root ganglion (DRG) neurons in mice. Pharmacologic studies demonstrated that the efficacy of the blood-brain-barrier (BBB) permeable Nav1.7 inhibitor GNE-0439 for attenuation of NP in SCI mice was significantly better than that of the BBB non-permeable Nav1.7 inhibitor PF-05089771. Moreover, more than 20% of Nav1.7-expressing SDH neurons in SCI mice were activated to express FOS when there were no external stimuli, suggesting that the ectopic expression of Nav1.7 made SDH neurons hypersensitive and Nav1.7-expressing SDH neurons participated in central sensitization and in spontaneous pain and/or walking-evoked mechanical pain. Further investigation showed that NGF, a strong activator of Nav1.7 expression, and its downstream JUN were upregulated after SCI in SDH neurons with similar distribution patterns and in DRG neurons too. In conclusion, our findings showed that the upregulation of Nav1.7 was induced by SCI in both SDH and DRG neurons through increased expression of NGF/JUN, and the inhibition of Nav1.7 in both peripheral and spinal neurons alleviated mechanical pain in SCI mice. These data suggest that BBB permeable Nav1.7 blockers might relieve NP in patients with SCI and that blocking the upregulation of Nav1.7 in the early stage of SCI via selective inhibition of the downstream signaling pathways of NGF or Nav1.7-targeted RNA drugs could be a strategy for therapy of SCI-induced NP.

项与 Nav1.7 antisense oligonucleotide (Q-State Biosciences) 相关的新闻（医药）

2022-01-19

·BioSpace

SiteOne Therapeutics Announces Collaboration and License Agreement with Vertex Pharmaceuticals to Advance NaV1.7 Inhibitors for the Treatment of Pain

SiteOne Therapeutics, a clinical-stage biopharmaceutical company developing non-opioid treatments to address pain, cough and other conditions involving hypersensitivity of the nervous system, today announced that it has entered into a strategic collaboration and licensing agreement with Vertex Pharmaceuticals. Under the terms of the agreement, the companies will work together to advance potent and selective inhibitors of sodium ion channel 1.7 (NaV1.7) as non-opioid therapeutics for the treatment of pain. SiteOne will be responsible for research and early preclinical development activities, with Vertex responsible for subsequent development, and commercialization. SiteOne will receive an upfront payment and is eligible for development, regulatory and commercial milestone payments, and royalties from Vertex if the program succeeds. "Pain is an extremely common medical condition that severely affects quality of life. The existing standard of care for pain treatment relies heavily on opioid analgesics, which are not always effective and carry a high risk of side-effects, dependence, and abuse. A core mission of SiteOne is to identify non-opioid pain medicines that will be able to safely and effectively treat many different types of pain and other neurological conditions without the risk of dependence or abuse," said John Mulcahy, Ph.D., CEO of SiteOne. "We are excited to begin this partnership with Vertex, which has a long-standing interest in non-opioid analgesic drug development. This agreement will support the advancement of SiteOne's portfolio of exquisitely-selective NaV1.7 inhibitors across multiple indications." NaV1.7 is a type of sodium channel that is highly expressed in peripheral nerve fibers that play a critical role in the generation and conduction of pain signals. The peripheral nervous system (PNS) is responsible for alerting the body against surrounding harmful stimuli. However, following insult or injury, the PNS often becomes sensitized, resulting in acute or chronic hypersensitivity disorders such as, pain, itch, and cough. About SiteOne Therapeutics SiteOne Therapeutics is a clinical-stage biopharmaceutical company advancing novel therapeutics targeting NaV1.7, NaV1.8 and other ion channels to treat hypersensitivity disorders. Since its inception, SiteOne has been dedicated to the development of safe and effective pain therapeutics without the significant addiction potential and side effects of opioids. The company is also advancing additional novel drug candidates that exhibit precise selectivity for individual sodium channel subtypes to treat other hypersensitivity disorders such as chronic cough and chronic ocular surface pain. SiteOne's therapeutic candidates are highly selective ion channel modulators.

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100 项与 Nav1.7 antisense oligonucleotide (Q-State Biosciences) 相关的药物交易

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